Study Sheds Light on the Natural History of Pediatric Nonalcoholic Steatohepatitis

A study of pediatric and adolescent patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) found that more than one-third experienced disease progression within two years, despite standard-of-care lifestyle counseling.

“This finding reinforces the need for physicians to have an increased index of suspicion when a child is at risk for this potentially serious condition. These patients need to be screened, counseled, educated and followed closely,” says pediatric gastroenterologist, Physician-in-Chief of Cleveland Clinic Children’s and President of Cleveland Clinic Children’s Hospital for Rehabilitation Karen Murray, MD, one author of the study published in Gastroenterology.

The study also highlighted that standard of care for these patients is not sufficient to stop the disease from progressing or turn it around.

“We must do a better job of educating families and supporting them in making lifestyle choices that encourage a healthy weight starting at a young age,” she says.

New information comes to light

The study compared paired liver biopsies from 122 children with NAFLD who had been treated with placebo and standard-of-care lifestyle advice in two randomized, double-blind clinical trials conducted by the NASH Clinical Research Network between 2005 and 2015.

“Studies on the natural progression of NASH are limited, and this study was a unique opportunity to follow the same patients over a period of time,” says Dr. Murray.

In less than two years, 18% of children with fatty liver (without NASH) or with borderline NASH developed NASH, and fibrosis worsened in 23%. These findings intrigued Mohammad Nasser Kabbany, MD, a pediatric NAFLD expert on at Cleveland Clinic Children’s.

“Generally speaking, adults take a decade to move from one stage of fibrosis to the next. Seeing a small but notable fibrosis progression in one-fourth of patients within two years was surprising,” he says.

The study also revealed NASH phenotypes to be dynamic.

“Two distinct histological phenotypes exist among children. The most common one includes zone 1 of the liver—called type 2 NASH—as opposed to the adult type, which involves zone 3 of the liver (type 1 NASH). In this study, half of the patients with pediatric phenotype transitioned to the adult phenotype, providing evidence these are not distinct phenotypes, but a continuum,” he says.

A two-way street

While more than one-third of participants experienced disease progression, the study also showed that NASH and fibrosis can be reversed. Over the study period, borderline or definite NASH resolved in 29% of patients, and mild fibrosis at baseline improved in 34%. However, the prevalence of fibrosis stages 2 and 3 remained stable. “Perhaps a longer time is needed to see regression in more advanced fibrosis,” says Dr. Kabbany.

A family problem

In one-third of patients, the development of liver disease was associated with a rise in body mass index (BMI), which occurred in 55%.

“Cultural perceptions of weight may be partly responsible for the fact that some families ‘get it,’ and others don’t,” says Dr. Murray. “Some families of a child with a BMI in the 90th percentile perceive it as normal, when it is not. We need to do better job of effectively communicating what a healthy weight is and how to achieve and maintain it.”

Improving success rates

The speed at which disease progression occurred reinforces the need for at-risk patients to be screened without delay. Guidelines for which patients should be screened and which tests should be ordered can be found here.

Although the goal of the study was not to evaluate the effectiveness of the standard intervention, it clearly revealed that seeing the patients every three months was insufficient to effect change. “It highlighted the importance of providing intense intervention,” says Dr. Kabbany.

The most effective weight management programs use a multidisciplinary team approach involving subspecialists, dietitians, psychologists, exercise physiologists and social workers, who spend a minimum of 25 hours over six months with the child and family.

“The problem is that these programs are so resource intensive, and not adequately reimbursed, that sustaining them is a challenge,” says Dr. Murray.

What’s next?

The study filled some knowledge gaps on the natural history of NASH, while opening others.

One area needing more research is the role of genes in NASH. Only one genotype was investigated in this trial, yet children who develop NAFLD at a young age may have different genetic propensities for the disease.

Genes may be the reason why Hispanic children showed a higher risk of fibrosis progression.

“Studies of genes other than PNPLA3 may shed light on why NASH progresses faster in certain patients than in others,” says Dr. Kabbany.

Moreover, the Hispanic children in this study were primarily Mexican. Whether the course of the disease would differ in other Hispanic groups has yet to be explored.

Dr. Kabbany is conducting research into the possible role of low choline bioavailability in preventing the liver from eliminating fat in children with NAFLD. He hopes the findings will add to understanding of the disease process.

“This study was a valuable addition to our knowledge. It’s good information to have,” he says.